Oral hygiene composition

ABSTRACT

Oral hygiene composition containing in combination chitosan and a sulphated, negatively charged polysaccharide in a biologically active amount; a process of improving oral hygiene in a mammal including man; and use of chitosan in combination with a sulphated, negatively charged polysaccharide for the manufacture of dentally active oral hygiene compositions.

The present invention relates to oral hygiene compositions containing incombination certain polysaccharide components, a process to improve oralhygiene in mammals including man and the use of combinations ofpolysaccharides for the manufacture of dentally active oral hygienecompositions.

Even if the present invention relates in general to oral hygiene it willprimarily be illustrated in connection with periodontitis, i.e. socalled teeth loosening, and measures aiming at reducing active plaque,i.e. bacterial deposits on the surface of the tooth.

Periodontitis is a collagen disease resulting in decomposition of thesupporting tissue of the tooth, periodontal ligaments and bone tissue.This results in weakening of the attachment apparatus, finally resultingin loosening of the tooth. The tooth loosening procedure isinflammatoric and the cause is found in the bacterial plaquesaccumulated on the surface of the tooth and against which the immunedefense of the body is not capable of adequate defense. P The symptomsin periodontitis is generally in an early stage an inflammatoric changeof the gingiva, i.e. the gums, which swells, reddens and becomes lightlybleeding on probing. In the transit from gingivitis to periodontitis,the latter constituting the destructive part of the cause of thedisease, the collagenous threads surrounding the attachment, theperiodontium, are destroyed, and simultaneously plaques spread down intothe periodontal pocket developed during the course of the disease. Thisresults in deepening and inflammation of the pocket, and as thepathological periodontal pocket deepens the tooth loses more and more ofits attachment thereby obtaining increased mobility.

The traditional treatment of the disease conditions mainly aim towardsactive plaques, i.e. bacterial deposits on the surface of the tooth. Theself-care of the patient in the form of thorough oral hygiene is ofdecisive importance in this connection. Usually the mechanical oralhygiene, tooth brushing, and interstitial hygiene using thread or stick,is the most common and effective procedure. However, there are differentchemical possibilities of affecting or preventing bacerial growth orbacterial adherence to the tooth.

Professional tooth cleaning using a tooth hygienist and/or a dentist whoremoves plaque present and cleans the deep periodontal pocketsinaccessible through common tooth cleaning reduces or eliminates theinflammation. If such cleaning of the tooth does not give the desiredeffect when carried out through the opening of the periodontal pocket asurgical treatment must be carried out. The gums are then folded asideso as to give full access to the pocket thereby enabling thoroughcleaning.

By means of different membranes the tissues can be kept apart during thecourse of healing and the tissue which is desired in healing will haveprecedence. This techniques are named "Guided Tissue Regeneration",abbreviated GTR. GTR-treatment is presently the only way of providingperiodontal healing with renewed growth of periodontal supportingtissue. Since the healing process is controlled by a barrier givingpriority to the slow periodontal ligament tissue, it is also conceivableto affect the process by means of substances that can affect theregenerative rate thereof.

Oral compositions for the treatment of inter alia caries,periodontoclasia and foul breath are known. For example, GB,A, 2132889discloses such oral compositions containing chitosan. Furthermore, oralcompositions to inhibit or prevent periodontoclasia and cariescontaining certain sulphated polysaccharides are previously known fromWO,A1, 8404453.

It is also previously known to combat plaque using certain negativelycharged polysaccharides, such as from EP,A1, 0 324 720 and GB,A,2215730.

Pharmaceutical compositions, inter alia in the form of a gel, forexample for non-topical wound treatment containing one, two or severalglycose aminoglykans, such as heparin, condroitin sulphate and chitosan,are previously known from WO,A1, 9312801. Furthermore, hypoglycaemiccompositions for oral administration containing oligo- orpolysaccharides of natural origin and derivatives thereof, such aschitosan, condroitin sulphates and heparin, are previously known fromSTN International, File WPIDS, STN accesion No. 84-198108, JP,A,59112922. Finally, from Chemical Abstracts, Vol. 121 (No. 3, 18 Jul.1994) abstract No. 26652, Vopr. Med. Khim., 1994, 40 (2), page 37-39 itis known that the combination of chitson sulphates and heparin affectthe activity of lipoprotein lipase.

The present invention has for its purpose to provide new techniques forimproved oral hygiene. Another object of the invention is to provide neworal hygiene compositions which substantially improve the conditions toalleviate the inflammatoric process in periodontitis and also to providerecreation of the attachment of the tooth.

Yet another purpose of the invention is to provide oral hygienecompositions which reduce the formation of active plaques on the surfaceof the tooth.

A further object of the invention is to provide a process to improveoral hygiene in mammals including man.

Yet another object of the invention is to provide use of certainpolysaccharides in combination for the manufacture of dentally activeoral hygiene compositions.

For these and other objects which will be clear from the followingdisclosure there is provided through the present invention an oralhygiene composition which in combination comprises chitosan and asulphated, negatively charged polysaccharide in a biologically activeamount.

In the composition according to the invention it is preferred that theweight ratio chitosan:sulphated polysaccharide lies within the rangeabout 6:4 to 95.5:0.5.

Among useful polysaccharides in oral hygiene compositions according tothe present invention there may be mentioned heparin, sucralfat,condroitin-6- or -4-sulphates, dermatan sulphate, keratan sulphate andpentosan sulphates.

It is particularly preferred in the oral hygiene composition accordingto the invention to use chitosan in combination with heparin, the weightratio between these two components preferably lying within the rangeabout 10:1 to 99.5:0.5.

The oral hygiene composition according to the present invention suitablycontains chitosan and sulphated polysaccaride in combination with adentally acceptable carrier. The oral hygiene composition can bepresented in the form of a tooth cream, a tooth paste or in the form ofa tooth powder. It may also be presented in the form of a mouth wash orin the form of a mouth spray. Finally, the oral hygiene compositionaccording to the invention can be presented in the form of degradablefilms, gels, pearls or powders.

The composition according to the present invention is preferably inaccordance with one aspect of the invention presented in the form of atooth cream, a tooth paste or a tooth powder. As an alternative thecomposition can also be presented in the form of a chewing gum, atablet, a lozenge or the like. Compositions of these types have, inaddition to the special combination of chitosan and a sulphated,negatively charged polysaccharide, a composition corresponding to theconventional techniques in the art. The special combination of thechitosan and sulphated polysaccharide in accordance with the presentinvention is present in the composition in a suitable minor amount,preferably from about 1 to about 25 percent by weight and particularlyfrom about 5 to about 15 percent by weight based on the composition as awhole.

When the composition is presented in the form of a tooth treatmentagent, such as tooth paste, it may also include a grinding agent inaccordance with conventional techniques. Such grinding agents can betaken from the traditional tooth agent techniques and be constituted byfor example silica, alumina, hydroxyapatite, plastic particles ormixtures thereof. The grinding agent is present in the composition in aminor amount, preferably within the range 5 to 25 percent by weight.

The composition according to the present invention may optionallycontain fluoro compounds for providing further anticaries effect. Suchfluoro-containing compounds are suitable of an ionic type and can beconstituted by a fluoride salt, such as an alkali metal fluoride. Amongpreferred fluorides there may be mentioned sodium fluoride but also thecorresponding potassium or litium salts can be used.

In a conventional manner the composition may furthermore containphosphates of different types in accordance with conventionaltechniques. Moreover, the composition according to the invention maycontain other excipients, such as surface active substances, gellingagents and other constituents, such as flavouring, sweetening andcolouring agents. Furthermore, the compositions according to theinvention, which are presented in the form of tooth paste, may containgelling agents, such as a natural or synthetic material. Among suchmaterials there may be mentioned natural gums, such as locust bean gum,guar gum, xanthan gum and the like. Even if such non-ionic gums arepreferred other materials may be used, for example tragant gum,sodiumcarboxymethyl cellulose, poly(vinylpyrrolidone), starch or thelike. Such gelling agents are contained in the composition in arelatively small amount, for example from about 0.01 to 3 percent byweight of the composition.

Oral hygiene compositions according to the invention in the form ofmouth washes can be presented as conventional gargles or can bepresented in the form of containers designed as oral spray devices.

Additionally, the compositions according to the invention can contain assweeteners for example saccarine, flavouring oils, such as peppermintoil, menthol, and colouring agents or white pigments, such as titaniumdioxide, preserving agents, for example bensoates, antibacterialsubstances, such as chlorohexidin.

According to another aspect of the invention there is provided also aprocess for improving oral hygiene in mammals including man, and in thisprocess there is administered orally to a mammal in need of treatment abiologically active amount of an oral hygiene composition as definedabove.

The process according to the invention is suitable for the treatment ofperiodontitis, plaques and/or caries.

According to yet another aspect of the present invention it resides inthe use of chitosan in combination with a sulphated, negatively chargedpolysaccharide for the manufacture of a dentally active oral hygienecomposition as has been defined above. It is particularly preferred inthis use that the chitosan is present in combination with heparin.

The expression "minor amount" used in the present disclosure inconnection with proportions between constituents present refers to anamount less than about 50 percent by weight based on the composition asa whole.

The present invention will in the following be further illustrated bynon-limiting examples, wherein percentages or proportions refer toweight unless otherwise indicated.

MATERIALS USED

Chitosan

Chitosan is a linear 1.4-bound polysaccharide built from free andN-acetylated β-D-glucosamine units. It is manufactured byN-deacetylation of chitin, a polymer forming the shell of inter aliainsects and crab fish. The degree of deacetylation can be controlled byhydrolysis using alkali. In the present case the chitosan is used in theform of commercially available hydrochloric salts of about 20%, 50% and85% N-deacetylation.

Sulphated polysaccharides

The preferred polysaccharide is the proteoglycane heparin (Pig mucosa,Kabi Vitrum) and other polysaccharides used are of a commercial typeavailable on the market.

EXAMPLE 1

Film of chitosan-heparin

5 g HCl salt of chitosan of 50% deacetylation (Pronova Biopolymers,Seacure C1 411) or of 85% deacetylation (Pronova Biopolymers, Seacure C1313) are dissolved in distilled water (0.5 L, 1% w/v). The film isprepared in petri-dishes having a surface of 54 cm². 20 mL of thesolution is poured into the bowl and the film is then allowed to dry ina drying cabinet at 70° C. for 16 h. The film is then neutralized usinga sodium phosphate buffer, 0.2M, pH 9, added to the petri-dish at roomtemperature. The film is allowed to stay in the buffer for 3-4 h and isthen washed 3-4 times using 50 mL distilled water and is allowed to dryat room temperature.

A heparin solution is prepared according to the following:

To 100 mL 0.15M sodium chloride there is added 25 mg nitrite degradedheparin (Pig mucosa, Kabi Vitrum). The pH is adjusted to 3.9 using 0.1Mhydrochloric acid, and 5 mg sodium cyanoborohydride are added to thesolution. The chitosan film is left in this solution under shaking overnight. The film is then washed with 50 mL distilled water 3-4 times.

EXAMPLE 2

Gel pearls of chitosan-heparin

A solution (2% w/v) of chitosan of 85% deacetylation (PronovaBiopolymers, Seacure C1 313) is drop-wise pumped through a capillary(0.8 mm inner diameter) down into a sodium phosphate buffer, 0.1M, pH 7,250 mL. Gel pearls of chitosan having a diameter of about 1.2 mm areformed.

After filtering on a glass filter and drying, the diameter of the ballsis reduced to about 0.8 mm. Heparin is attached to the balls byionbinding by admixing heparin, 1 g/L, in the buffer used.

EXAMPLE 3

Gel of chitosan-methyl cellulose-heparin

100 mg heparin are added to 100 mL distilled water with mixing. To thesolution obtained there are added 50 mL of an aqueous solution of methylcellulose (2% w/v) under stirring. To the solution obtained there isthen added 50 mL chitosan (2% w/v, 50% deacetylation) also understirring. Stirring is maintained for another 10 minutes, a coherent gelbeing obtained.

EXAMPLE 4

Film of chitosan-heparin, covalently bound

A neutralized chitosan film made in accordance with the description ofExample 1 is immersed in 20 mL of a solution wherein it is allowed toremain for 24 h. The solution consists of 4,4 g sodium chloride and 125mg periodate oxidized heparin in 0.5 L of water. The pH is adjusted to3.9 with 0.5M hydrochloric acid, and then 15 mg of sodiumcyanoborohydride is added. The film treated in this manner is thenwashed with water 3-4 times and is allowed to dry.

EXAMPLE 5

Film of chitosan-heparin, ion bound

To a neutralized chitosan film made in accordance with Example 1 thereis added 20 mL of a solution consisting of 125 mg heparin dissolved in0.5 L of water containing 4.4 g sodium chloride, the pH being adjustedto 3.9 with the use of 0.5M hydrochloric acid. Film and solution areallowed to stand in room temperature for 14 h. The film obtained is thenwashed with water 3-4 times and allowed to dry.

EXAMPLE 6

Tooth paste

A tooth paste is prepared as follows:

    ______________________________________                                        Ingredients        Percentage                                                 ______________________________________                                        Sugar solution (50% solution                                                                     25                                                         of sorbitol, saccarin)                                                        Glycerol           8                                                          Titanium dioxide   1.5                                                        Thickening agent, silica                                                                         5                                                          Grinding agent, alumina                                                                          12                                                         Surfactant                                                                    Flavour            0.5                                                        Gel according to Example 3                                                                       10                                                         Water              37                                                                            100                                                        ______________________________________                                    

The ingredients above are mixed in a suitable apparatus in aconventional manner whereafter, if necessary, the pH is adjusted toabout neutral.

EXAMPLE 7

Tooth powder

Heparin (Pig mucosa) in pulverulent form is admixed with chitosan (50%deacetylation, Pronova Biopolymers, Seacure C1 411) to form afine-grained dry powder useful as an oral hygiene composition.

EXAMPLE 8

Mouth wash

    ______________________________________                                        Ingredients        Percentage                                                 ______________________________________                                        Ethanol            8                                                          Glycerol           4                                                          Flavours           0.1                                                        Gel according to Example 3                                                                       5                                                          Water              82.9                                                                          100.0                                                      ______________________________________                                    

The ingredients are mixed in the proportions given to form a slightlycloudy mouth wash.

EXAMPLE 9

Clinical test of tooth powder

The tooth powder according to Example 7 is used in connection with toothbrushing daily for 2 months for the purpose of studying the influence onthe general tooth status and the condition of the periodontal pockets ofthe subject under test. The result after two months tooth brushing wasthe following according to the evaluation made by tooth technicians:

    ______________________________________                                        Periodontal pockets  Pocket depth                                             ______________________________________                                        10 pockets           1 mm deeper                                              31 pockets           unchanged                                                45 pockets           1 mm reduction                                            6 pockets           2 mm reduction                                            4 pockets           3 mm reduction                                            3 pockets           4 mm reduction                                           ______________________________________                                    

Furthermore, no visible inflammation could be observed and, in addition,X-rays taken of the front teeth of the subject indicate newly formedtissue around the teeth. Since the development of periodontal pockets toan increased depth normally in accordance with conventional art can beretarded but rarely reversed the results presented above are unexpectedand essential.

EXAMPLE 10

Clinical test using tooth paste

The test according to Example 9 is repeated, this time using the toothpaste manufactured according to Example 6. The results obtained aresimilar to those obtained in Example 9. Furthermore, there is obtainedas a result of the modified brushing of the teeth a clearplaque-reducing effect in relation to normal teeth brushing using normaltooth paste. This reduction of plaque results in a clear regression ofthe gingival inflammation, and a distinct mobility reduction could alsobe observed.

EXAMPLE 11

Clinical test using film

In relation to a factual periodontal pocket a surgical incision wasperformed residing in cutting, after anaesthesia, with a scalpel in thegingiva along the outside of the tooth and the inside the tooth in thearea involved. The gingiva is folded out from the tooth and the rootsurface of the tooth having plaque deposited thereon is exposed. Theroot surface is now cleaned with an instrument for removal of plaque,and after cleaning and washing using sterile solutions thechitosan-heparin film made in accordance with Example 1 is appliedlocally, and the gingiva is then stitched back onto the surface of thetooth.

In connection with healing reduced inflammation, reduced pathologicalpocket depth, reduced mobility and improved attachment by X-ray could beobserved.

EXAMPLE 12

Clinical test using gel pearls

The procedure in Example 11 is repeated, in this instance while usinggel pearls of chitosan-heparin manufactured according to Example 2.Similar results are obtained.

EXAMPLE 13

Clinical test using gel

The procedure of Example 11 is repeated, this time while using the gelof chitosan-methylcellulose-heparin prepared according to Example 3.Similar results to those of Example 11 can be observed.

EXAMPLE 14

Mouth-wash

Example 8 is repeated while using dermatan sulphate as a sulphatedpolysaccharide instead of heparin.

EXAMPLE 15

Clinical test using tooth powder

Example 9 is repeated in this case using a tooth powder according toExample 7 wherein heparin is replaced with condroitin-6-sulphate.

EXAMPLES 16-20

Test for antibacterial activity using solutions

The following solutions are prepared:

1) Dextransulphate (Pharmacia, 1 g) is dissolved in 200 mL of distilledwater. To the stirred solution are added 50 mL of an aqueous solution ofmethylcellulose (2% w/v) and 250 mL of chitosan (2% w/v, with a degreeof deacetylation of 59% ).

2) To water (200 mL) are added 50 mL of an aqueous solution ofmethylcellulose (2% w/v) and 250 mL of chitosan (2% w/v, with a degreeof deacetylation of 59%).

3) Heparin (1 g) is dissolved in 200 mL of distilled water. To thestirred solution are added 50 mL of an aqueous solution ofmethylcellulose (2% w/v) and 250 mL of chitosan (2% w/v, with a degreeof deacetylation of 59%).

4) Heparin (Pig mucosa, Kabivitrum, 1 g) is dissolved in 450 mL ofdistilled water. To the stirred solution is added 50 mL of an aqueoussolution of methylcellulose (2% w/v).

5) Dextransulphate (Pharmacia, 1 g) is dissolved in 450 mL of distilledwater. To the stirred solution is added 50 mL of an aqueous solution ofmethylcellulose (2% w/v).

The solutions are tested for antibacterial activity in blood bowlscoated with saliva diluted 1:10 and dried in an incubator for 30 minbefore use. Longitudinal grinding sections of teeth exposing enamel andcement are immersed in the respective test solutions for 5 min at 37° C.and then transferred to sterile physiological salt water for up to 3 h.At 0 min, 15 min, 30 min, 1 h, 2 h, 3 h one grinding section from eachtest series is removed and placed on two coated blood bowls. A negativecontrol is placed in the centre of each bowl.

The antibacterial activity of the respective solutions is evaluatedaccording to a score from 0 to 3. Solutions 1, 2 and 3 of Examples 16,17 and 18, respectively, are selectively antibacterial after 30 minrinsing and keep their antibacterial activity during the test period of3 h. The results are summarized in the following table.

                  TABLE                                                           ______________________________________                                        Example         Solution                                                                              Score                                                 ______________________________________                                        16              1       3                                                     17              2       2                                                     18              3       3                                                     19              4       0                                                     20              5       0                                                     ______________________________________                                    

It can be seen from the table above that using solutions containing onlyheparin or dextran sulphate in addition to mehtylcellulose express noobservable anti-bacterial activity, whereas solutions combining eitherchitosan and dextran sulphate or chitosan and heparin show the highestscore. Since, in addition to methylcellulose, solely chitosan shows alower score the test results indicate a synergistic effect by thecombination of chitosan and the sulphated negatively chargedpolysaccharides.

As is clear from performed clinical tests the use of the techniquesaccording to the present invention induces essential and unexpectedimprovements in relation to the course of healing in connection withoral problems residing in periodontitis, formation of plaque and otherinflammatoric conditions. Even though the present invention is notregarded to be restricted to any particular scientific theory ormechanism of action it is conceivable that the main constituentschitosan and sulphated, negatively charged polysaccharide present in theoral hygiene composition have such effect on the bacterial flora in theoral cavity or result in such enrichment of growth factors that thedifferent healing processes are substantially promoted and accelerated.The invention is not restricted to the preferred embodiments asexemplified and the scope of the invention is limited only by theappended claims.

What is claimed is:
 1. A method for the treatment of periodontitis,plaque or dental caries, said method comprising topically exposing theteeth or gums of a mammal in need of such treatment to an oral hygienecomposition comprising chitosan in combination with a sulphated,negatively charged polysaccharide and dentally acceptable carrier,wherein the amount of said composition is effective to treatperiodontitis, plaque or dental caries.
 2. The method according to claim1, wherein the weight ratio chitosan-polysaccharide lies within therange about 6:4 to 99.5:0.5.
 3. The method according to claim 1, whereinthe polysaccharide is selected from the group consisting of heparin,sucralfat, condroitin sulphates, dermatan sulphate, keratan sulphate andpentosan sulphates.
 4. The method according to claim 3, wherein thepolysaccharide is heparin.
 5. The method according to claim 1, whereinthe combination is in the form of a tooth cream, tooth paste or a toothpowder.
 6. The method according to claim 1, wherein the combination isin the form of a mouth wash.
 7. The method according to claim 1, whereinthe combination is in the form of a mouth spray.
 8. The method accordingto claim 1, wherein the combination is in the form of a degradable film,in the form of a gel, in the form of pearls or in the form of a powder.9. The method according to claim 1, wherein the chitosan is present incombination with a polysaccharide selected from the group consisting ofheparin, sucralfat, condroitin sulphates, dermatan sulphate, keratansulphate and pentosan sulphates.
 10. The method according to claim 9,wherein the chitosan is present in combination with heparin.
 11. Themethod according to claim 2, wherein the polysaccharide is selected fromthe group consisting of heparin, sucralfat, condroitin sulphates,dermatan sulphate, keratan sulphate and pentosan sulphates.
 12. Themethod according to claim 2, wherein the combination is in the form of adegradable film, in the form of a gel, in the form of pearls or in theform of a powder.
 13. The method according to claim 3, wherein thecombination is in the form of a degradable film, in the form of a gel,in the form of pearls or in the form of a powder.
 14. The methodaccording to claim 4, wherein the combination is in the form of adegradable film, in the form of a gel, in the form of pearls or in theform of a powder.
 15. The method according to claim 11, wherein thecombination is in the form of a degradable film, in the form of a gel,in the form of pearls or in the form of a powder.
 16. An oral hygienecomposition for the treatment of periodontitis, plaque or dental caries,said composition comprising an effective amount to treat periodontitis,plaque or dental caries of chitosan in combination with a sulphated,negatively charged polysaccharide and a dentally acceptable carrier.